tbuckley/cabot-search huggingface dataset:
Abstract 3900: <i>In vivo</i> inhibition of metastatic HER2 positive trastuzumab resistant breast cancer using engineered destabilized 3UTR ARE of HER2 improves survival outcomes
Authors: Chidiebere U. Awah, Joo Sun Mun, Baris Boylu, Alooka Paragodaarachchi, Chika Ochu, Hiroshi Matsui, Olorunseun O. Ogunwobi
Journal: Cancer Research (2023)

Abstract Breast cancer is the most common form of cancer in women with mortality of about 58% in developing countries. HER2+ breast cancers are treated with trastuzumab in various forms in combination with chemotherapy and has been successful in targeting HER2 overexpression in HER2+ breast cancer and improving survival as a standard first line therapy for more than a decade. However, about 25% of early and 75% of late stage HER2 driven breast cancers are resistant to trastuzumab. For these patients, the clinical outcomes are grim. We report the destabilization of HER2 3‘UTR ARE which degraded oncogene HER2 transcript, protein expression, HER2 dependent kinases and interactome. In vitro, we transfected the engineered destabilizing HER2 constructs into BT474 clone 5 trastuzumab resistant breast cancer and within days, we inhibited cancer cell growth and degraded HER2 transcript and protein. The degradation of HER2 leads to loss of many kinases especially YES1 and WNK1 that are known causes of chemoresistance in HER2 positive trastuzumab resistant breast cancer. In vivo, we administered the destabilizing constructs as naked constructs or as complexed with nanocages to mice bearing tumors of BT474 clone 5 trastuzumab resistant cells. We found that our constructs, both the naked and nanocage-delivered, conferred significant survival (p values: 0.0178 and 0.00492) to about 60% of the exceptionally surviving mice compared to the controls. Taken together, we have developed a new therapy to target trastuzumab resistant HER2+ metastatic breast cancers with increased survival outcomes. Citation Format: Chidiebere U. Awah, Joo Sun Mun, Baris Boylu, Alooka Paragodaarachchi, Chika Ochu, Hiroshi Matsui, Olorunseun O. Ogunwobi. In vivo inhibition of metastatic HER2 positive trastuzumab resistant breast cancer using engineered destabilized 3UTR ARE of HER2 improves survival outcomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3900.
Abstract 3299: Usefulness of protocadherin GA12 and cysteine ​​dioxygenase type 1 methylation biomarkers in the diagnosis of lung cancer
Authors: Ji Woong Son, Minhyeok Lee, In Beom Jeong, Sun Jung Kwon, Daeun Kang, Moon Jun Na
Journal: Cancer Research (2023)

Abstract Rationale: The use of bronchoscopy is key to the diagnosis of lung cancer. However, the sensitivity of bronchoscopy is low. In addition, bronchial washing cytology, a routine auxiliary test, does not significantly improve the performance of bronchoscopy due to its low sensitivity. To improve the diagnostic performance of bronchoscopy, protocadherin GA12 (PCDHGA12) and Cysteine ​​Dioxygenase Type 1 (CDO1) methylation biomarkers in bronchial washing fluid have been introduced as novel adjunctive diagnostic tests. Methods: A total of 161 patients with suspected lung cancer who underwent bronchoscopy were analyzed. Cytological examination of bronchial washing fluid and testing for PCDHGA12 and CDO1 methylation biomarkers were performed. Results: The final diagnosis was lung cancer in 114 patients, and benign disease in 49 patients. PCDHGA12 methylation biomarker showed sensitivity of 80.4% and specificity of 87.8%. CDO1 methylation biomarker showed sensitivity of 66.1% and specificity of 98.0%, whereas cytological evaluation showed sensitivity of 43.8% and specificity of 100%. The combined analysis of PCDHGA12 and CDO1 methylation showed sensitivity of 84.8% and specificity of 85.7%. The combined analysis of the methylation biomarkers and cytology tests resulted in a slightly increased sensitivity of 86.6% and specificity of 85.7%. The specificity and sensitivity of the methylation biomarkers were also high in peripheral lung cancer. Conclusion: The results of this study demonstrated that PCDHGA12 and CDO1 methylation as lung cancer biomarkers of bronchial washing may be used as adjunctive tests for bronchoscopy. Keywords: biomarker; bronchoscopy; lung cancer; protocadherin GA12: CDO1, methylation Citation Format: Ji Woong Son, Minhyeok Lee, In Beom Jeong, Sun Jung Kwon, Daeun Kang, Moon Jun Na. Usefulness of protocadherin GA12 and cysteine ​​dioxygenase type 1 methylation biomarkers in the diagnosis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3299.
Abstract 3378: Rapid and efficient sample preparations for cell free DNA
Authors: Zhiyang Zeng, Andrew Taft, Kasen Riemersma, Connor Fitzgerald, Mike Scurria, Spenccer Hermanson, Wenhui Zhou
Journal: Cancer Research (2023)

Abstract The analysis of cell-free DNA (cfDNA) as a sensitive biomarker for cancer prognosis, diagnosis and monitoring resulted in a need for efficient and fast cfDNA isolation. The traditional cfDNA purification methods using chaotropic solvent to separate nucleic acids from plasma through column or magnetic bead purification processes are usually laborious and time consuming, involving multiple washing steps, and the residual organic solvent could be carried over to the elution solution that could cause downstream PCR inhibition. Herein, we developed a novel particle surface chemistry that can biochemically bind rapidly (&amp;lt;1min) and release nucleic acids rapidly (&amp;lt;1min) under different buffer conditions without needing chaotropic solvent. We further optimized the binding and elution buffer solutions that allow to isolate cfDNA from plasma within 5-10 minutes in the sample volumes from 1 ml to 4 ml. The real-time quantitative PCR indicated DNA extraction yields were comparable or slightly better than the traditional methods for both small and large volumes. The novel bead chemistry and the optimized binding and elution buffers are not only compatible to high throughput format but could also be applied to a variety sample types for rapid sample preparations. Citation Format: Zhiyang Zeng, Andrew Taft, Kasen Riemersma, Connor Fitzgerald, Mike Scurria, Spenccer Hermanson, Wenhui Zhou. Rapid and efficient sample preparations for cell free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3378.
Abstract 4104: Development of adoptive T-cell therapies to target heterogeneity of mCRPC
Authors: Lupita S. Lopez, Nathanael Bangayan, Owen Witte, Saul J. Priceman
Journal: Cancer Research (2023)

Abstract Metastatic castration resistant prostate cancer (mCRPC) remains a significant challenge with limited durable therapeutic responses, and innovative and effective treatment strategies are needed. Advanced mCRPC often comprises a heterogeneous population of prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC), and current targeted therapies often result in transient anti-tumor responses. Chimeric antigen receptor (CAR) T-cell therapies are being actively investigated to target mCRPC, including CARs targeting antigens that are overexpressed in PrAd. Our group has developed a CAR T cell targeting the PrAd antigen, prostate stem cell antigen (PSCA), and have an ongoing phase 1 trial at City of Hope in patients with mCRPC. However, we anticipate that targeting NEPC in addition to PrAd will be required to achieve durable anti-tumor responses in patients. Here, we have developed novel dual-targeting approaches for the simultaneous treatment of both PrAd and NEPC. Our first approach optimizes a tandem CAR T-cell approach capable of targeting distinct antigens found on both PrAd and NEPC. Additionally, we are actively developing combinations of PSCA-CAR T-cells with secretable T-cell bispecific antibodies to target NEPC antigens. Our studies encompass the in vitro and in vivo safety and efficacy of CAR T-cells engineered to co-target PrAd and NEPC for the treatment of heterogeneous mCRPC. Citation Format: Lupita S. Lopez, Nathanael Bangayan, Owen Witte, Saul J. Priceman. Development of adoptive T-cell therapies to target heterogeneity of mCRPC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4104.
Abstract 2337: Overcome solid tumor immunosuppression for T cells-mediated cancer elimination
Authors: Lei Shi, Zhen Bian, Jane Zen, Harry Stylli, Yuan Liu
Journal: Cancer Research (2023)

Abstract T cell immunotherapy to solid tumor requires not only sufficient numbers of cancer cell-specific cytotoxic T cells, but also their infiltration into tumor tissues and the ability to resist hostile TME immunosuppression. Through a proprietary process, we have identified a unique reagent, termed KX147, of which treatment of tumor potently repolarizes the TME, resulting in abrogation of multi-axes immunosuppressive signal transduction pathways reprograme of the TME for innate and adaptive immunity against cancer. We found that immunotherapy-refractory solid tumors under therapies generally fail to induce intratumoral macrophages for proinflammatory phenotypic change, nor did they reprogram the TME towards anti-tumor immunogenicity. Rather, these tumors arbitrate strong resistance through increasing IL-10 production, TGFβ signaling (TGFBR1 and TGFBR2), and CCL2 chemokine that attracts MDSC, leading to wound healing and reinforcement of tumor immunosuppression. In stark contrast, tumors treated with KX147 exhibit completely different TME responses to checkpoint blockade, RT and other immune-modulatory therapies, and reshape intratumoral macrophages from immunosuppression to potent proinflammation, featuring high expressions of TNFα, IFNγ, IL-1β, IL-6, IL-12, IL-17, IL-18, etc., while abating IL-10 and TGFβ. Moreover, KX147 also induces a prominent immunogenic antigen presentation machinery with elevated cell surface MHC-I, MHC-II, and costimulatory molecules CD80, CD86, CD40, OX40L on macrophages, which through antigen presentation induces large expansion of tumor-specific T cells for tumor elimination. Together, our studies demonstrate a novel immunotherapy strategy with KX147 combination, which holds promises for rapid and systemic elimination of solid tumors and metastases to achieve cure. Citation Format: Lei Shi, Zhen Bian, Jane Zen, Harry Stylli, Yuan Liu. Overcome solid tumor immunosuppression for T cells-mediated cancer elimination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2337.
Abstract 349: LncRNA <i>Myca</i> controls hepatocellular carcinoma growth and progression
Authors: Hsin-Yi Chen, Yu-Yun Weng, Wei-Chien Yuan, Yu-Ru Lee
Journal: Cancer Research (2023)

Abstract Long non-coding RNAs (lncRNAs) have been shown to play critical roles in the tumorigenesis and progression of cancer. From a clinic and genomic perspective of evidence, the MYC signaling plays a crucial role in triggering hepatocellular carcinoma (HCC) and therefore represents an attractive target for HCC intervention. However, no specific drug is currently available to target MYC directly due to the lack of an enzymatic pocket. Therefore, deciphering the critical lncRNAs that functionally crosstalk with MYC protein levels may offer novel therapeutic strategies in HCC. Here we identify the involvement of a lncRNA Myca (Myc Activator) in HCC through controlling MYC protein levels. Overexpression of Myca triggers tumor growth in a MYC-dependent manner, while inactivation of Myca by antisense oligonucleotides (ASOs) profoundly reduces MYC protein levels, thus suppressing tumor progression in vitro. Mechanistically, we show that Myca attenuates MYC ubiquitination and leads to MYC accumulation. Clinically, overexpression of Myca is positively correlated with Hi-MYC transcriptional profile and HCC progression from the TCGA dataset. Together, our findings not only identify Myca in controlling MYC protein levels but also provide Myca as a new therapeutic lncRNA target for the HCC intervention. Citation Format: Hsin-Yi Chen, Yu-Yun Weng, Wei-Chien Yuan, Yu-Ru Lee. LncRNA Myca controls hepatocellular carcinoma growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 349.
Abstract 328: Acetylation regulates the oncogenic functions of PRMT5
Authors: Tam Thuy Lu Vo, Yen Thi Do, Thi Tuyet Mai Pham, So-Jin Shin, Jin Young Kim, Seungmee Lee, Eunyoung Ha, Ji Hae Seo
Journal: Cancer Research (2023)

Abstract Protein arginine methyltransferase 5 (PRMT5) is an enzyme responsible for symmetric arginine methylation, which governs multiple crucial cellular events. PRMT5 expression and activity are dysregulated in many malignancies. PRMT5 dynamically shuttles between the cytosol and nucleus, and different subcellular localizations of PRMT5 imposes distinct cellular functions. However, the biological significance and underlying regulatory mechanism of PRMT5 translocation remain elusive. Herein, we found that PRMT5 acetylation/deacetylation status is a major determinant of its translocation and oncogenic function. PRMT5 acetylation not only drives its cytoplasmic localization but also enhances its methyltransferase activity, promoting cancer cell proliferation. On the other hand, PRMT5 deacetylation translocates PRMT5 into nucleus, to protect cells under the stress condition. Our current findings demonstrate that the acetylation/deacetylation-dependent subcellular localization of PRMT5 is a key regulator of its oncogenic properties. Citation Format: Tam Thuy Lu Vo, Yen Thi Do, Thi Tuyet Mai Pham, So-Jin Shin, Jin Young Kim, Seungmee Lee, Eunyoung Ha, Ji Hae Seo. Acetylation regulates the oncogenic functions of PRMT5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 328.
Abstract 6575: LinkedOmicsKB: A web portal to explore pan-cancer molecular and phenotype associations
Authors: Sara R. Savage, Yuxing Liao, Yongchao Dou, Zhiao Shi, Xinpei Yi, Wen Jiang, Jonathan T. Lei, Bing Zhang
Journal: Cancer Research (2023)

Abstract Pan-cancer multi-omics data produced from integrated genomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) profiling of a wide variety of cancer types holds great potential for understanding cancer biology and generating therapeutic hypotheses. To realize this potential and make analysis and visualization of these complex and interconnected data easily accessible to cancer biologists and clinicians, we have developed a web portal, LinkedOmicsKB. The web portal provides access to a harmonized proteogenomic dataset of over 1000 patient samples covering 10 cancer cohorts from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We calculated associations between methylation, copy number variation (CNV), RNA, protein, and phosphosite data for each gene and further correlated the proteogenomics data with clinical and computed molecular phenotypes. All results are stored in a MongoDB database and visualizations are provided for exploring pan-cancer multi-omics relationships as well as individual statistics. We demonstrate the utility of LinkedOmicsKB to provide insights into clinical phenotypes, somatic mutations, and understudied genes. In the pan-cancer CPTAC data, overall survival was correlated with proteins involved in protein hydroxylation, including PLOD1 and PLOD2. Additionally, two phosphorylation sites on the tumor suppressor MIG-6 were associated with worse survival. These sites were also associated with hypoxia, MAPK, and EGFR pathway activity scores, suggesting a relationship between the signaling in these pathways and cancer prognosis. STK17B is an understudied kinase that regulates apoptosis. We found STK17B was upregulated in 6 cancer types at the protein level but only two at the RNA level. The protein abundance of STK17B was highly associated with immune scores and JAK/STAT signaling, supporting a role for STK17B in the immune response. We identified 3 phosphorylation sites on STK17B, which were associated with EGF pathway activity scores and immune-related scores. LinkedOmicsKB is a valuable tool that can be used to generate biological and clinical insights into any gene, phosphosite, mutation, or phenotype. Citation Format: Sara R. Savage, Yuxing Liao, Yongchao Dou, Zhiao Shi, Xinpei Yi, Wen Jiang, Jonathan T. Lei, Bing Zhang. LinkedOmicsKB: A web portal to explore pan-cancer molecular and phenotype associations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6575.
Abstract 5029: Determining the biological function of TNK1
Authors: Emmalee Kohler, Tania Lopez-Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua Andersen, D. Madhusanka
Journal: Cancer Research (2023)

Abstract Thirty-eight-negative kinase 1 (TNK1) is a poorly characterized member of the ACK family of non-receptor tyrosine kinases, which we recently identified as a driver of cell survival in a subset of primary hematological malignancies. However, the biological function of TNK1 is not well understood. We also found that TNK1 is unusual among kinases for the presence of a functional ubiquitin association (UBA) domain on its C-terminus. We discovered that the TNK1 UBA domain binds to poly-ubiquitin with high affinity and has no apparent preference for ubiquitin chain length or linkage type. Interestingly, the UBA domain is important for TNK1 function, given that deletion of the UBA domain (TNK1 ΔUBA) alters its localization and phospho-substrate network, while also weakening the oncogenic activity of TNK1 in cell transformation assays. Based on these data, we hypothesized that the UBA domain tethers TNK1 to its substrates. To test this hypothesis, we performed quantitative phospho-tyrosine proteomics using murine pro-B cells transformed with either TNK1 full length or TNK1 ΔUBA and identified TANK-binding kinase 1 (TBK1) as a putative UBA-dependent TNK1 substrate. TBK1 is a serine/threonine kinase involved in the regulation of inflammation, autophagy, and NF-ĸB signaling. During the selective autophagic degradation of misfolded proteins (aggrephagy), TBK1 phosphorylates p62 at S403 to increase its affinity to ubiquitin, and thereby increases p62-mediated recruitment of misfolded proteins into the condensate. Unchecked growth of ubiquitin condensates can overwhelm the size capacity of autophagosomes, potentially causing misfolded proteins to become proteotoxic aggregates. Our preliminary data suggest a model in which active TNK1 accumulates at ubiquitin condensates to phosphorylate and inhibit TBK1. Based on these data, we propose that TNK1 acts as a kinase sensor of poly-ubiquitin to control the TBK1-mediated growth of ubiquitin condensates. Citation Format: Emmalee Kohler, Tania Lopez-Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua Andersen, D. Madhusanka. Determining the biological function of TNK1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5029.
Abstract 4848: Effects of cinnamon extracted under acidic conditions on proliferation of MCF7 cells
Authors: Madison Anderson, Amy Stockert
Journal: Cancer Research (2023)

Abstract Recent evidence suggests that MCF7 cells utilize free fatty acids as a primary energy source by increasing lipase activity in neighboring adipocytes. Research in our lab suggests that lipase activity is increased by cinnamon extract in differentiated 3T3-L1 adipocytes. We hypothesized that since co-cultures between adipocytes and MCF7 cells demonstrated an increase in lipase activity and increased proliferation, cinnamon extract may increase proliferation of MCF7 cells, making cinnamon an important ingredient to avoid in patients with breast cancer. Cells were plated and treated with varying amounts of cinnamon and monitored for proliferation using the MTT assay. Cells consistently, albeit not significantly, showed an increase in proliferation when treated with cinnamon. Additional studies need to be completed in order to confirm these effects and look for significance, although the importance of this finding warrants rapid reporting. Our lab will examine the effects of cinnamon extract at varying concentrations on MCF7 cell proliferation under variable media conditions as well as monitoring the lipase activity in the MCF7 cells. Citation Format: Madison Anderson, Amy Stockert. Effects of cinnamon extracted under acidic conditions on proliferation of MCF7 cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4848.